PEGylation but Not Fc-Fusion Improves in Vivo Residence Time of a Thermostable Mutant of Bacterial Cocaine Esterase

Formulation and evaluation of effervescent floating tablets of tizanidine hydrochloride Tizanidine hydrochloride is an orally administered prokinetic agent that facilitates or restores motility through-out the length of the gastrointestinal tract. The objective of the present investigation was to develop effervescent floating matrix tablets of tizanidine hydrochloride for prolongation of gastric residence time in order to overcome its low bioavailability (34-40 %) and short biological half life (4.2 h). Tablets were prepared by the direct compression method, using different viscosity grades of hydroxypropyl methylcellulose (HPMC K4M, K15M and K100M). Tablets were evaluated for various physical parameters and floating properties. Further, tablets were studied for in vitro drug release characteristics in 12 hours. Drug release from effervescent floating matrix tablets was sustained over 12 h with buoyant properties. DSC study revealed that there is no drug excipient interaction. Based on the release kinetics, all formulations best fitted the Higuchi, first-order model and non-Fickian as the mechanism of drug release. Optimized formulation (F9) was selected based on the similarity factor (f2) (74.2), dissolution efficiency at 2, 6 and 8 h, and t50 (5.4 h) and was used in radiographic studies by incorporating BaSO4. In vivo X-ray studies in human volunteers showed that the mean gastric residence time was 6.2 ± 0.2 h.

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Preclinical Assessment of Nanostructured Liquid Crystalline Particles for the Management of Bacterial Keratitis: in-vivo and Pharmacokinetics Study

10.21203/rs.3.rs-481365/v1 ◽

2021 ◽

Author(s):

Shreya Kaul ◽

Upendra Nagaich ◽

Navneet Verma

Keyword(s):

Residence Time ◽

Liquid Crystalline ◽

Ex Vivo ◽

Research Work ◽

Poloxamer 407 ◽

Pharmacokinetic Studies ◽

Eye Drops ◽

Statistical Experimental Design ◽

Bacterial Keratitis

Abstract The research work was driven to develop novel nanostructured liquid crystalline particles of vancomycin for its improved pre-ocular residence time, ocular bio-availability, enhanced targeting, increased permeability, reduced dosing frequency, controlled drug release and reduced systemic side-effects. Formulation was developed by fragmenting cubic crystalline phase of glycerol monooleate, water and poloxamer 407. A four-factor, three-level Taguchi statistical experimental design was constructed to optimize the formulation. Formulations exhibited internal-cubic structure of the vesicles with particle size in the range of 51.11 ± 0.96 nm to 158.73 ± 0.46 nm and negative zeta potential. Ex-vivo transcorneal permeation studies demonstrated that the optimized cubosomes had 2.4-fold increase in apparent permeability co-efficient as compared to vancomycin solution. Whereas, in-vivo studies in rabbits demonstrated that the severity of keratitis was considerably lowered in day 3 with optimized cubosomes. Ocular pharmacokinetic studies evaluated level of drug in aqueous humor and results revealed that the time to peak concentration (Tmax) of vancomycin loaded cubosomal formulation was about 1.9-fold higher and mean residence time was 2.2-fold greater than vancomycin solution. Furthermore, histological examination revealed that the corneal layers displayed well-maintained morphology without any stromal swelling, consequently indicating safety of formulation. In conclusion, results manifested that the developed vancomycin loaded cubosomes could be a promising novel ocular carrier and an ideal substitute for conventional eye-drops for the management of bacterial-keratitis.

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Single molecule tracking of Ace1p in Saccharomyces cerevisiae defines a characteristic residence time for non-specific interactions of transcription factors with chromatin

Nucleic Acids Research ◽

10.1093/nar/gkw744 ◽

2016 ◽

Vol 44 (21) ◽

pp. e160-e160 ◽

Cited By ~ 23

Author(s):

David A Ball ◽

Gunjan D Mehta ◽

Ronit Salomon-Kent ◽

Davide Mazza ◽

Tatsuya Morisaki ◽

...

Keyword(s):

Transcription Factors ◽

Residence Time ◽

Single Molecule ◽

Specific Binding ◽

Underlying Mechanism ◽

Specific Interactions ◽

Single Molecule Tracking ◽

Reliable Performance ◽

Transient Interactions

Abstract In vivo single molecule tracking has recently developed into a powerful technique for measuring and understanding the transient interactions of transcription factors (TF) with their chromatin response elements. However, this method still lacks a solid foundation for distinguishing between specific and non-specific interactions. To address this issue, we took advantage of the power of molecular genetics of yeast. Yeast TF Ace1p has only five specific sites in the genome and thus serves as a benchmark to distinguish specific from non-specific binding. Here, we show that the estimated residence time of the short-residence molecules is essentially the same for Hht1p, Ace1p and Hsf1p, equaling 0.12–0.32 s. These three DNA-binding proteins are very different in their structure, function and intracellular concentration. This suggests that (i) short-residence molecules are bound to DNA non-specifically, and (ii) that non-specific binding shares common characteristics between vastly different DNA-bound proteins and thus may have a common underlying mechanism. We develop new and robust procedure for evaluation of adverse effects of labeling, and new quantitative analysis procedures that significantly improve residence time measurements by accounting for fluorophore blinking. Our results provide a framework for the reliable performance and analysis of single molecule TF experiments in yeast.

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Prolonging the In Vivo Residence Time of Prostaglandin E1 with Biodegradable Nanoparticles

Pharmaceutical Research ◽

10.1007/s11095-008-9549-8 ◽

2008 ◽

Vol 25 (7) ◽

pp. 1686-1695 ◽

Cited By ~ 27

Author(s):

Tsutomu Ishihara ◽

Miyuki Takahashi ◽

Megumu Higaki ◽

Mitsuko Takenaga ◽

Tohru Mizushima ◽

...

Keyword(s):

Residence Time ◽

Prostaglandin E1 ◽

Biodegradable Nanoparticles

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Chitosan inhibits platelet-mediated clot retraction, increases platelet-derived growth factor release, and increases residence time and bioactivity of platelet-rich plasma in vivo

Biomedical Materials ◽

10.1088/1748-605x/aa8469 ◽

2017 ◽

Vol 13 (1) ◽

pp. 015005 ◽

Cited By ~ 9

Author(s):

Gabrielle Deprés-Tremblay ◽

Anik Chevrier ◽

Nicolas Tran-Khanh ◽

Monica Nelea ◽

Michael D Buschmann

Keyword(s):

Growth Factor ◽

Residence Time ◽

Platelet Rich Plasma ◽

Platelet Derived Growth Factor ◽

Clot Retraction ◽

Growth Factor Release ◽

Factor Release

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HA-based dermal filler: downstream process comparison, impurity quantitation by validated HPLC-MS analysis, and in vivo residence time study

Journal of Applied Biomaterials & Functional Materials ◽

10.1177/2280800019867075 ◽

2019 ◽

Vol 17 (3) ◽

pp. 228080001986707 ◽

Cited By ~ 2

Author(s):

Cristian Guarise ◽

Carlo Barbera ◽

Mauro Pavan ◽

Susi Panfilo ◽

Riccardo Beninatto ◽

...

Keyword(s):

Residence Time ◽

Rabbit Model ◽

Diglycidyl Ether ◽

In Vitro Cytotoxicity ◽

Dermal Filler ◽

Dermal Fillers ◽

Process Comparison ◽

Hygroscopic Properties

The success of hyaluronic acid (HA)-based dermal fillers, with more than 2 million minimally invasive procedures conducted in 2016 in the US alone, is due to their hygroscopic properties of biocompatibility and reversibility. The type and density of HA cross-linkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 1,4-Butanediol diglycidyl ether (BDDE) is the cross-linker used in most market-leading HA fillers; 1,4-butanediol di-(propan-2,3-diolyl) ether (BDPE) is the major impurity obtained from the HA–BDDE cross-linking (HBC) process. In this work, a new process to obtain high purity HBC fillers was developed. A new HPLC-MS method was validated for the quantification of BDPE content in HBC dermal fillers. In vitro cytotoxicity of BDPE was evaluated in fibroblasts (IC50 = 0.48 mg/mL). The viscoelasticity was monitored during the shelf-life of the HBC-10% hydrogel and was correlated with in vitro hyaluronidase resistance and in vivo residence time in a rabbit model. This analysis showed that elasticity is the best parameter to predict the in vivo residence time. Finally, a series of parameters were investigated in certain marketed dermal fillers and were compared with the results of the HBC-10% hydrogel.

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Kinetics of Drug Binding and Residence Time

Annual Review of Physical Chemistry ◽

10.1146/annurev-physchem-042018-052340 ◽

2019 ◽

Vol 70 (1) ◽

pp. 143-171 ◽

Cited By ~ 22

Author(s):

Mattia Bernetti ◽

Matteo Masetti ◽

Walter Rocchia ◽

Andrea Cavalli

Keyword(s):

Computational Methods ◽

Residence Time ◽

Drug Target ◽

Early Stage ◽

Kinetic Constant ◽

Theoretical Background ◽

Drug Binding ◽

Binding Kinetics ◽

Kinetics Of

The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/ koff). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy). There are many experimental and computational methods for predicting drug-target residence time at an early stage of drug discovery programs. Here, we review and discuss the methodological approaches to estimating drug binding kinetics and residence time. We first introduce the theoretical background of drug binding kinetics from a physicochemical standpoint. We then analyze the recent literature in the field, starting from the experimental methodologies and applications thereof and moving to theoretical and computational approaches to the kinetics of drug binding and unbinding. We acknowledge the central role of molecular dynamics and related methods, which comprise a great number of the computational methods and applications reviewed here. However, we also consider kinetic Monte Carlo. We conclude with the outlook that drug (un)binding kinetics may soon become a go/no go step in the discovery and development of new medicines.

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